Ethical considerations in conducting clinical trials for elderly cancer ...

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PERSPECTIVE

Ethical considerations in conducting clinical trials for elderly cancer patients Antonella Surbone Department of Medicine, New York University, 530 First Avenue, NY 10016, USA E-mail: [email protected]

Keywords: agism, caregivers, clinical trials, costs, culture, ethics, frailty, geriatric oncology part of

Under-representation of the elderly in clinical trials leads to inadequate information on the effect of age with regard to new anticancer treatments. The exclusion of elderly patients from cancer experimentation, often due to limiting medical or psychosocial factors, appears to also stem from misconceptions about aging and frailty. Limited data on elderly cancer patients enrolled in clinical trials suggest that age itself, in the absence of severe concomitant illnesses or psychological, cognitive or functional impairment, is not an independent risk factor for either increased toxicity or lack of treatment efficacy. Prospective benefits of inclusion of the elderly in clinical trials must be weighed against exposing individual patients to potential risks. The medical, ethical and methodological implications of experimentation in the elderly need to be studied in depth. This article reviews ethical issues in cancer clinical trials, focusing on aspects that may deserve special attention when elderly patients are enrolled.

Owing to aging of the population and increased cancer incidence, in May 2005 the World Health Organisation approved a resolution on worldwide cancer prevention and control [1]. The population of elderly persons, arbitrarily defined as adults aged 65 years and older, is increasing in developed and developing countries. In the USA, it is projected to almost double from 37 million to 70 million between 2005 and 2030 [2]. The elderly, who currently comprise 12% of the US population, account for more than of a third of all hospital stays and prescriptions and more than a fourth of all office visits to physicians, and the average 75-year old American has three or more comorbidities and takes at least four types of medication [3]. In addition, 60% of all cancer cases in western countries are diagnosed in people over 65 years of age, two-thirds of cancer mortalities occur in this age group and 60% of the 10.8 million US cancer survivors are over 65 years of age [4–6]. Owing to medical, social and cultural factors, elderly cancer patients tend to be subjected to less screening and prevention and to be diagnosed later in the disease process, undergo less rigorous cancer staging, are often undertreated and experience lower survival rates [7–11]. Elderly cancer patients also tend to be excluded from clinical trials. Studies show that while over 60% of cancers occur in patients over 65 years of age, and 35% occur in patients over 75 years of age, in western countries, only 25 and 10% of these patients are enrolled in clinical trails, respectively [12–16]. The elderly tend to be excluded from clinical trials for a variety of

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reasons related to patients’ and physicians’ perceptions, comorbidities and social and cultural factors (Box 1). Clinical trials are the most reliable research method in oncology for establishing the efficacy of new medical, surgical or radiation therapies while rejecting unsafe or ineffective ones, and for confirming or discounting the benefits of existing treatments and making accurate comparisons among them. According to the US FDA, to properly assess their risks and benefits, drugs should be studied in all age groups for which they will be used [17]. The under-representation of elderly patients in clinical trials, therefore, represents an unfair exclusion not supported by evidence of inherent differences in treatment toxicity and effectiveness for different age groups, and it impairs our ability to generalize research findings, inhibiting the development of adequate therapeutic modalities in geriatric oncology. Many international agencies and institutions, including the National Institute of Aging, the American Society of Clinical Oncology and the International Society of Geriatric Oncology, as well as a number of US and European cooperative study groups, have begun to systematically question old assumptions and prejudices in geriatric oncology, transforming it into an active field of research, education and organizational change [18–22]. Studying the medical, social, economic and ethical barriers to the recruitment of elderly cancer patients in clinical trials, and the possible ways to overcome them, is essential in order to create a Aging Health (2008) 4(3), 253–260

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Box 1. Reasons for exclusion of elderly cancer patients from clinical trials. • • • • • • • • •

Patients’ reluctance to participate due to fear of toxicity that could affect quality of life Patients’ mistrust and reluctance to participate in human experimentation Patients’ inability to provide informed consent due to physical or mental impediments Physicians’ reluctance to enrol patients owing to perceived unfavorable cost–benefit ratio Physicians’ reluctance to enrol patients owing to belief that age correlates with increased toxicity Physicians’ reluctance to enrol patients owing to concomitant illnesses Lack of logistic and social support for patients (transportation and home assistance) Limited financial resources of many elderly patients Limited resource allocation to the elderly population

new culture of geriatric oncology [23]. The focus of this article is on the ethical implications of clinical research that are magnified in geriatric oncology because of the higher vulnerability of elderly persons, and that are influenced by the meaning and value that societies attribute to aging. Old age: biological reality or sociocultural construct? In western countries, old age tends to be represented only in terms of decreased productivity, functional impairment, comorbidity, cognitive limitations and the burden of care placed on the family and/or the healthcare system. Aging involves a progressive decline in the functional reserve of multiple organs and systems that modulate the person’s adaptation to stress [24]. Comorbidity, disability and frailty are known to occur in elderly patients as separate entities [25]. Despite the lack of a unanimous definition of frailty, the multidimensional conceptualization of frailty developed and applied in geriatric medicine takes into consideration the interplay of physical, psychological, cognitive, functional, social and environmental factors [26,27]. Assessment of frailty from a multidimensional perspective provides an important guide to clinical decision making in geriatric oncology, as the patient’s frailty often limits the safety of administration of standard and experimental cancer treatments. By contrast, when frailty results from the patient’s cancer, active treatment could improve or even reverse it [28,29]. Frailty is exacerbated by a lack of social support, and elderly cancer patients are at risk for diminished quality of life and increased psychological stress. Contrary to common belief, however, psychosocial studies and meta-analyses indicate that elderly people respond more positively than younger adults to the experience of cancer, owing to greater life experience, ability to use internal resources and past experience coping with difficult life situations [30,31]. 254

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When evaluating whether or not to enrol elderly patients in clinical trials, variables that contribute to frailty should be taken into proper consideration, and stereotypical cultural judgements that interfere with clinical decisions regarding age must be avoided. In this regard, comprehensive geriatric assessment of the physical, psychological, cognitive and functional status of individual elderly patients should be conducted to identify those patients at high risk of complications from cancer therapies who should not be enrolled in clinical trials [32–35]. Even during the course of standard treatments, or among elderly patients deemed to be eligible for clinical trials, objective clinical measurements and unbiased judgement of the presence of cognitive impairments are critical for providing good care to elderly patients who may require home assistance or special supportive measures during cancer treatment [36]. Optimal supportive and palliative care and accurate measure of quality of life in elderly cancer survivors are prerequisites for the effective delivery of standard and experimental therapies in geriatric oncology [37]. Ethical implications of clinical trials Our understanding of the ethics of human experimentation, based on the Nuremberg Trial, involves respect for universal human dignity, equal access to healthcare and research resources and the right to self determination [38]. There is consensus in the medical, ethical and legal literature on clinical trials, that the scientific design of clinical trials should be sound and unbiased and that ethical standards should be applied consistently [39,40]. Value, scientific validity, fair subject selection, favourable risk–benefit ratio, independent review, informed consent and respect for potential and enrolled subjects are basic ethical requirements in clinical research [41]. Professional integrity of physicians who are also investigators or who treat patients enrolled in future science group

Ethical considerations in clinical trials for elderly cancer patients – PERSPECTIVE

clinical trials is the ‘the most reliable safeguard’ against more or less overt abuses in human experimentation [42]. Maintaining professional integrity as clinicians who are also conducting research requires integration of the roles of clinician and scientist, along with understanding of, and respect for, the ethical complexities and ambiguities involved in clinical research, in order to face the moral challenges posed by competing interests and loyalties in clinical research [39]. In geriatric oncology, certain ethical domains appear magnified or carry special nuances, owing to the increased dependence and vulnerability of elderly patients and to social prejudices with regard to aging in western societies. As an example, respect for patients’ autonomous informed decisions is a well-established principle in western medicine in both clinical care and research. Patients’ participation and withdrawal to clinical trials should be voluntary and uncoerced [43,44]. Autonomy, however, relates not only to people’s rights to make personal choices, but also to their ability to enact their choices on the basis of internal and external resources (Box 2) [45,46]. Older patients, for example, are often more dependent on external resources than their younger counterparts, and they tend to ask for less information and to delegate decisions to their doctors or caregivers [47]. Informed consent is often reduced to a mere procedure rather than an educational process, and written forms may lack clarity and comprehensibility for patients or even oncologists [48]. Assurance of the quality of informed consent is especially important with regard to elderly patients, whose physical, intellectual and functional abilities to read, comprehend and absorb the content of lengthy and wordy forms may be compromised. Involvement of patients and patient advocates in establishing research priorities in clinical trial is key to their ethical conduct, but such practice is rare in geriatric oncology. Economic implications, in terms of costs and conflicts of interests, are also a major consideration in the ethics of clinical trials in geriatric oncology [49]. Box 2. Factors influencing autonomy in elderly cancer patients. • • • •

Loss of productivity and consequent life roles Degrees of social integration or isolation Degrees of physical and social independence Availability and accessibility of community resources (transportation, companionship and home help) • Presence or absence of family support

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Resource allocations & costs in clinical trials for the elderly Enrolment of elderly patients in clinical trials is often seen as being ineffective both cost- and treatment-wise, owing to the lower life-expectancy of the geriatric population; increased vulnerability associated with frequent concomitant illnesses and functional disabilities that may influence toxicity and efficacy of experimental therapies; increased needs for supportive care and assistance; and higher indirect and intangible costs of clinical trials in the elderly (indirect costs related to loss of productivity and income and intangible costs of the compromised personal well-being of caregivers) [49]. In addition, caring for elderly cancer patients enrolled in clinical trials can be complex and time-consuming for physicians, nurses and hospital staff. Finally, the need for home assistance is higher for elderly cancer patients, as they are often functionally dependent on others. For these reasons, physicians and policy makers have long wondered whether the elderly should be included in clinical trials. Yet results of clinical trials that included elderly patients show no significant differences in this group with respect to toxicity and drug efficacy [13,15,16]. A review of 33 Phase II studies involving single agents for different cancers showed no significant differences in performance status, number of dose reductions, treatment interruptions and days of delay, incidence of grade III–IV toxicity, reasons for off-study or best response [50]. While enrolled patients were highly selected and an upper age limit of 70 years was used in most studies, available data suggest that age per se should not be a criterion for exclusion of the elderly from clinical trials in oncology [23,51]. In view of the medical and ethical considerations discussed above, it appears that clinical trials can and should enrol more elderly patients. Cost containment is an important consideration, but it should be based on valid, reliable, transparent and unbiased cost analysis. Costs and charges are different and their analysis is never independent of perspectives and free from value judgments [49,52,53]. As charges are the most accessible data, costs are generally assessed in terms of charges incurred by providers, hospitals and pharmacies. Costs, the nonnegotiable element of charges, are different for each party involved in clinical trials [49]. The perspectives of the scientific community, the medical community, medical institutions and 255


individual physicians or investigators differ, and all of these taken together differ from those of patients, families, communities and the society at large. Once diverse views and interests are openly acknowledged and discussed, participating parties may be able to reach consensus on which costs are bearable and on whether the burden of those costs is distributed on the basis of justice, fairness and common sense [49,52,53]. To properly assess costs of clinical trials in geriatric oncology, it is necessary to recognize and analyze different components of costs and their relative impact in elderly cancer patients (Box 3). With respect to direct and indirect medically related costs, for example, these may be ameliorated by early institution of adequate supportive therapies and by timing of hospitalization, which assure that elderly patients will be discharged when completely stable [49]. The costs of managing complications at home, in fact, can rapidly escalate in the case of elderly patients at risk of worsening functional dependence. These costs will be imposed on caregivers, with deep repercussions on their lives in terms of lost productivity and compromised wellbeing [47,49]. Consideration of the emotional and economic contribution of caregivers, along with research that explores the influence of social support and family functioning on patient coping and adaptation, and on gender differences in caregiving in elderly cancer patients, are ethical priorities in geriatric oncology [54,55]. Methods currently used to control costs include bedside rationing, financial incentives, markets-based insurance, cost-sharing with patients, and cost–effectiveness analysis coupled with adjustments for quality of life. From practical and ethical standpoints, current strategies for making decisions about resource allocation are not neutral. By contrast, the development of an open, public, participatory process with a commitment to common sense rationality shared by all partners is a sound ethical approach to cost containment in oncology that would not affect the fiduciary nature of the patient–doctor relationship and would allow physicians to be partners with, and advocates for, their patients [53]. Box 3. Costs components. • • • •

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Direct medical costs Indirect medically related costs Indirect medically unrelated costs (productivity) Intangible costs (repercussions on caregivers)


Aging, culture & patient autonomy The distorted cultural perception of age that dominates most western societies, known as agism, has a major influence on our attitudes toward, and practice of, healthcare for elderly cancer patients [47]. Elderly persons in contemporary western societies tend to have reduced opportunities to be involved in their communities, to have lower incomes and to be underserved with respect to healthcare. The correlation between aging and low socioeconomic status negatively impacts on elderly patients’ health status and on their access to care and research. Poverty is common in the elderly, and socioeconomic factors combined with cultural ones in ethnic minorities in western countries render access to clinical trials for elderly persons extremely difficult [56]. Within multiethnic societies, cultural differences influence patients’ views of illness and suffering, of the patient–doctor relationship, of trust in institutions and in medical science and attitudes toward experimental therapies. Age contributes to cultural and generational differences with respect to health values [47,57]. Culture also influences both the understanding and the expression of ethical norms in clinical practice. In addition, the value attributed to individual patient autonomy varies across different cultures [58]. In many cultures, for example, autonomy is still traditionally perceived by elderly patients as synonymous with isolation, not with empowerment [49,59]. Autonomy has been understood in western cultures only in terms of an individual’s right to make choices based on adequate information. Contemporary moral philosophy and bioethics, however, have unveiled the multiple external and internal limitations to individual autonomy and developed the notion of relational autonomy [45,46]. In oncology, for example, patients’ decisions about treatment, palliative and end-of-life care are never based only on the information they possess, but also on socioeconomic status, education, family and community support, and cultural values and attitudes [47]. Additional factors that may influence an elderly persons’ dependency and autonomy are shown in Box 2. Despite possible limitations, elderly persons are capable of retaining personal autonomy in their lives as long as they are competent, and paternalism toward them, even in weak forms, should be avoided [47]. Indeed, a leading cause of underrepresentation of the elderly in clinical trials future science group


comes from physicians’ making decisions for their elderly cancer patients on the presumption that they neither want nor can tolerate aggressive or new therapies, or that they are less compliant than younger patients [60–62]. Conclusion The ethics of clinical trials in elderly cancer patients is based upon the same considerations and principles of scientific and moral integrity that rule the design and conduct of all human experimentation. There is no a priori scientific or ethical justification for not offering clinical trials to elderly cancer patients, not implementing and conducting specific clinical trials in geriatric oncology or not investing sufficient resources to geriatric oncology. Older adults are often excluded from clinical trials because of profound misconceptions about their inherent frailty and inability to withstand cancer treatments. Hence, we must develop, improve, teach and apply proper methods to assess all variables that may contribute to frailty and increased risk of toxicity in elderly cancer patients, and we must deconstruct our prejudices about aging. Doing so will require active professional, moral and social engagement, aimed at a rational and humane reappraisal of the sociocultural meaning of older age in industrialized societies. We should, therefore, continue to address clinical, ethical, cultural, psychosocial and economic issues in providing standard and experimental cancer treatments to elderly patients, including the moderating effect of family and friends on emotional, cognitive and instrumental support to patients and their partners. Finally, we should demand healthcare policy changes, founded on an unbiased understanding of the medical and ethical implications of geriatric oncology. Clinical oncologists should continue to offer a range of therapies or clinical trials to their elderly patients in order to provide optimal care to them. Not all elderly cancer patients are frail, yet not all clinical trials are appropriate and safe even for fit elderly cancer patients. Geriatric oncology requires knowledge, expertise and sensitivity toward each elderly patient, whose clinical and contextual situation may be highly complex. Distinguishing clinical judgments based on sound evidence from cultural myths, biases or prejudices will lead to higher effectiveness and quality of standard and experimental treatments for our elderly cancer patients. future science group


Future perspective Given the rapid increase of the elderly population worldwide, caring for the elderly has become a priority for our societies and healthcare systems [3]. Geriatric oncology is a growing need in western societies and a new challenge for physicians and their patients and caregivers, as well as for institutions and policy makers. Providing optimal care to elderly cancer patients involves both the correct and wise use of standard treatments and the judicious enrolment of elderly persons in clinical trials. Scientific and ethical aspects of clinical research are inseparable, and representation of elderly cancer patients in clinical trials is respectful of the ethical requirements of justice in human experimentation, and critical for gathering information on how age affects toxicity and efficacy of experimental cancer drugs. As many of the barriers to enrolment of elderly cancer patients are patient related, these barriers should be studied and addressed [23]. Provision of social and community support to those who need home or travel assistance may be a means for increasing the participation of elderly cancer patients in clinical trials. Measures to alleviate protocol-related barriers are also under evaluation. These include revising current selection criteria to allow for the inclusion of elderly persons in clinical trials; focusing on experimentation of new therapies that may reasonably benefit elderly cancer patients without excessive harm; and assessing elderly patients for medical comorbidities and cognitive and functional impairments prior to treatment decisions. They also include using geriatric-assessment instruments that are validated and feasible in the clinical oncology setting; modulating dose escalation through incremental steps on the basis of tolerance in elderly patients; designing innovative clinical studies tailored to the geriatric population for highly prevalent cancers; and testing single agents or combinations to study specific aspects of pharmacokinetics and pharmacodynamics in elderly patients [60–64]. The timely use of supportive care and rehabilitation measures during the course of cancer treatment is also needed. The unbiased evaluation of individual patients’ life expectancy and of their understanding and desires with respect to cancer treatment is essential, along with the identification and application of adequate outcome measures of physical, mental, functional and social variables [65,66]. Education of professionals and patients is key to progression in the field of geriatric oncology and to the ethical conduct of clinical trails in the elderly [67,68]. Additionally, we need to give high priority to research on socioeconomic 257


determinants of quality of life in the elderly with respect to patients’ safety and sources of family and community support, and to study the particular communication needs, preferences and styles of elderly cancer patients and their families [69,70]. Acknowledgement I am grateful to Mr William Russell-Edu, Librarian at the European Institute of Oncology in Milan, Italy for his valuable assistance in preparing the manuscript.

Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Executive summary • As the world population ages and cancer incidence increases, adequate healthcare resources should be allocated to geriatric oncology, including the participation of elderly persons in clinical trials. • Age is not only a biological reality but also a sociocultural construct. Older adults tend to be excluded from clinical trials owing to misconceptions about their putative frailty and inability to withstand cancer treatments. • Empirical studies suggest that it is a misconception to consider age as an independent factor for toxicity and efficacy of experimental therapies, and psychosocial studies show that elderly patients tend to adapt to stressful events better than younger people. • The ethical conduct of clinical trials is based on scientific validity, professional integrity and fairness in access to experimentation, and these principles apply equally to geriatric oncology. • Current under-representation of elderly patients in clinical trials is ethically unfair and also medically unsound, as it inhibits our ability to test and develop proper therapies in geriatric oncology. • Enrolment of elderly cancer patients in clinical trials requires proper assessment of each elderly patient’s physical, mental, emotional and functional status. • Unbiased cost analysis is required to identify potential areas of cost containment that do not prejudice the elderly’s access to clinical trials in oncology. • Patient autonomy should be respected and paternalism toward elderly patients avoided. At the same time, cultural and social factors that may influence elderly patients’ dependency or autonomy must be assessed and taken into consideration. • Deconstruction of agism and attention to the role of caregivers must be addressed in the immediate future in regard to participation of elderly patients in clinical trials.

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